A key dilemma facing clinical organ and tissue grafting is the shortage of donor tissues for transplantation. This problem requires the consideration of tissues from other species (xenografts) as a potential alternative supply of donor material. While antibody-dependent hyperacute rejection provides a major barrier to the transplantation of discordant solid-organ xenografts, the rejection of cellular xenografts - such as pancreatic islets - appears to be initiated by T cell-dependent immunity. The aim of this proposal is to clarify the nature of cellular immunity/tolerance to xenogeneic pancreatic islets as a model of cellular xenografting. Establishing the basic requirements for xenogeneic T cell immunity and tolerance is necessary for directing the future clinical application of cellular xenografting. The nature of cellular immunity to xenogeneic tissues remains unclear as illustrated by an important paradox of xenoreactivity: Vigorous cell- mediated rejection of xenografts occurs in vivo despite the finding that the intensity of the T cell-dependent response to xenogeneic antigen presenting cells (APC) in vitro tends to decrease as the phylogenetic disparity between responding and stimulating species increases. Specific Aim I of this proposal attempts to reconcile this paradox by testing the working hypothesis: Cellular allograft rejection depends heavily on 'direct' (donor APC-dependent) T cell activation while xenograft rejection depends heavily on 'indirect' (host APC-dependent) T cell activation. The test of this hypothesis and its implications will be by: (1) Determining the phenotype(s) of unprimed versus primed lymphocytes and/or antibodies necessary to reconstitute islet allograft versus xenograft immunity in severe-combined-immune-deficient (SCID) mice, (2) Examine the ability of defined xenoreactive T cell lines/clones to mediate xenograft immunity in vivo, (3) Determine whether xenograft immunity is MHC-restricted in vivo, (4) Determine whether inflammatory tissue damage contributes to islet allograft versus xenograft rejection in vivo, and (5) Determine whether rejection of islet xenografts is donor APC-dependent in vivo. The hyporeactivity of xenogeneic responses in vitro is attributed, in part, to deficiencies in the inter-species T cell-APC interaction. These deficiencies which affect T cell activation may also affect tolerance induction to xenoantigens. Specific Aim II of this proposal addresses this issue by testing the hypothesis: Efficient tolerance induction to peripheral (extrathymic) transplantation antigens requires CD8 or CD4 co- receptor interaction with MHC molecules. This hypothesis will be tested by: (1) Determining whether maturing T cells will develop tolerance to islet allografts versus xenografts where the inter-species CD8-class I MHC is deficient, and (2) Determining whether genetically eliminating the CD8-class I MHC interaction will preclude peripheral tolerance to MHC class I alloantigens.